AUREOBASIDINS

Abstract: Aureobasidins useful as a wide-spectrum antimycotic. They are cyclodepsipeptides composed of one hydroxy acid residue having group A¹, three amino acid residues having groups C¹, F¹ and H¹, four N-methylamino acid residues having groups B¹, D¹, G¹ and I¹, and one cyclic amino acid residue having E¹. A representative example thereof is one wherein A¹ is CH₃CH₂CH(CH₃)-, B¹ is (CH₃)₂CH-, C¹ is benzyl, cyclohexylmethyl, p-fluorobenzyl, benzyloxymethyl, benzyloxybenzyl, methoxybenzyl, cyclohexylmethyloxybenzyl, etc., D¹ is methyl, benzyl, hydroxymethyl, etc., E¹ is propylene, F¹ is CH₃CH₂CH(CH₃)-, G¹ is (CH₃)₂CH-, H¹ is (CH₃)₂CHCH₂-, and I¹ is (CH₃)₂C(OH)-. They have excellent activities against not only candida but also cryptococcus and aspergillus.

Description: TECHNICAL FIELD This invention relates to Aureobasidins which are of value as the therapy of fungal infections. PRIOR ART Fungi infect internal organs and brain to induce systemic mycosis or the skin, oral cavity and other tissues to induce superficial mycosis in man. They also cause similar infections in pet, domestic and other animals. It is also known that fungi cause a variety of diseases in plants such as orchard trees and vegetables. The principal causative agents of systemic mycosis in man are fungi of the genus Candida , those of the genus Cryptococcus , and those of the genus Aspergillus . Superficial mycosis in man are caused by fungi of the genus Candida (infecting the skin, oral cavity, vagina, etc.) or those of the genus Trichophyton (infecting the skin of the hand and foot). In addition, a broad spectrum of other fungi are members of the earth's ecology and are regarded as etiologic factors in many infections and pollutions in animals and plants. Against such fungal infections, a variety of counter-measures have been undertaken. A large number of antifungal agents are known that can be used for the treatment and prevention of fungal infections and pollutions but few are satisfactory enough in safety and efficacy. Among the therapeutic drugs heretofore available for systemic infections in man and animals are Amphotericin B, Flucytosine, Miconazole and Fluconazole but these drugs are not impeccable, either, in efficacy, toxicity and/or potential of expression of resistance. Particularly, only a very few drugs are available that can success fully control systemic infections which are steadily increasing in these years. Aureobasidins have been disclosed in, inter alia , Japanese Kokai Publication Hei-2-138296, Japanese Kokai Publication Hei-3-22995, Japanese Kokai Publication Hei-3-44398, Japanese Kokai Publication Hei-3-220199 (EP-A-443719), Japanese Kokai Publication Hei-5-279384, Japanese Kokai Publication Hei-6-65291 (EP-A-581 429), EP-A-500 264 and J. Antibiot. 46(9), 1347 (1993). Among the Aureobasidins described in the above literature are Aureobasidin A of the following structural formula (4) and its various analogs. In the above formula, D -Hmp represents 2(R)-hydroxy-3(R)-methylpentanoic acid. All the amino acids are L-types. Aureobasidin A is one of the most active and least toxic of all the known Aureobasidins and is active against many pathogenic fungi inclusive of Candida species. However, this substance is not sufficiently active against Aspergillus and not as active against Cryptococcus as against Candida, so that no sufficient therapeutic efficacy can be expected in infections associated with the former fungi. Many other Aureobasidins are also highly active against Candida but only weakly active against Cryptococcus and little active against Aspergillus . DESCRIPTION OF THE INVENTION This invention has for its object to provide a novel class of Aureobasidins which are broader in antifungal spectrum than the hitherto-known Aureobasidins. In summary, this invention relates to an Aureobasidin compound of general formula (1): wherein A 1 , B 1 , F 1 , G 1 and H 1 are the same or different and each represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms; C 1 represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, benzyloxymethyl, benzyl, a substituted benzyl, phenyl or a substituted phenyl (said substituted benzyl or substituted phenyl means benzyl or phenyl substituted by at least one substituent selected from the class consisting of a straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, benzyloxy and halogen); D 1 represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, hydroxymethyl or benzyl (where C 1 is benzyl o-fluorobenzyl or m-fluorobenzyl, D 1 is a group other than benzyl and hydroxymethyl); E 1 represents a straight-chain alkylene having 1 to 5 carbon atoms; I 1 represents a hydroxy-substituted lower alkyl having 1 to 6 carbon atoms. For the purpose of creating novel Aureobasidin compounds with improved activity against Cryptococcus and Aspergillus , the inventors of this invention synthesized various analogs by chemical synthesis and found that compounds of general formula (1) have higher activity than the known Aureobasidins against Cryptococcus and Aspergillus . This invention has been accomplished as a result. The compound of the general formula (1) is a cyclic depsipeptide consisting of one hydroxy acid residue having A 1 , 3 amino acid residues having C 1 , F 1 and H 1 , respectively, 4 N-methylamino acid residues having B 1 , D 1 , G 1 and I 1 , respectively, and 1 cyclic amino acid residue having E 1 . The above-mentioned I 1 has a hydroxy group. Said A 1 is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, preferably is (CH 3 ) 2 CH- or CH 3 CH 2 CH(CH 3 )-, and the hydroxy acids containing them are 2-hydroxy-3-methylbutanoic acid and 2-hydroxy-3-methylpentanoic acid, respectively. Said B 1 is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, preferably is (CH 3 ) 2 CH-, and the N-methyl amino acid containing it is N-methylvaline. Said C 1 is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, benzyl, substituted benzyl, phenyl or substituted phenyl. The lower alkyl of said C 1 includes, for example, CH 3 -, (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 -, CH 3 CH 2 CH(CH 3 )- and the like. The amino acids having them are alanine, valine, leucine and isoleucine, respectively, and leucine is preferred. Said cycloalkyl includes, for example, cyclohexyl, and cyclohexylmethyl. The amino acid having them are cyclohexylglycine and cyclohexylalanine, respectively, and cyclohexylalanine is preferred. The amino acid having benzyl or phenyl of said C 1 is phenylalanine and phenylglycine, respectively. Said benzyl or phenyl may have a substituent of straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, benzyloxy or halogen. Said lower alkoxy includes, for example, methyloxy, ethyloxy and the like, and methyloxy is preferred. Said cycloalkoxy includes, for example, cyclohexyloxy, cyclohexylmethyloxy and the like, and cyclohexylmethyloxy is preferred. Said halogen includes, for example, chloro, fluoro and the like, and fluoro is preferred. The amino acid having fluoro includes, for example, p-fluorophenylalanine. Said D 1 is straight-chain or branched lower alkyl having 1 to 6 carbon atoms, hydroxymethyl or benzyl. Said lower alkyl includes, for example, CH 3 -, (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 -, CH 3 CH 2 CH(CH 3 )- and the like. The N-methylamino acid containing them are N-methylalanine, N-methylvaline, N-methylleucine and N-methylisoloeucine respectively, and N-methylalanine and N-methylvaline are preferred. The N-methylamino acid containing said hydroxymethyl and said benzyl respectively is N-methylserine and N-methylphenylalanine. Aureobasidin according to this invention does not include the compound wherein C 1 is benzyl o-flurobenzyl or m-flurobenzyl, and D 1 is benzyl or hydroxymethyl. Said E 1 is a straight-chain alkylene having 1 to 5 carbon atoms and preferably, -(CH 2 ) 3 -, and the cyclic amino acid having this is proline. Said F 1 is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, preferably (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 - or CH 3 CH 2 CH(CH 3 )-, and amino acid having them are respectively, valine, leucine, isoleucine and alloisoleucine. Alloisoleucine is preferred. Said G 1 is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, preferably (CH 3 ) 2 CH-, and amino acid having it is N-methylvaline. Said H 1 is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, preferably (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 - or CH 3 CH 2 CH(CH 3 )-, and amino acid having them are respectively, valine, leucine, isoleucine and alloisoleucine. Leucine is preferred. Said I 1 is a lower alkyl having 1 to 6 carbon atoms substituted by hydroxy, preferably (CH 3 ) 2 C(OH)-. The N-methylamino acid having this is β-hydroxy-N-methylvaline. A typical example of Aureobasidins of general formula (1) includes compounds 1 to 12 shown in Table 1. In Table 1, " · " shows the same amino acid or hydroxy acid as that of compound 1. In said compounds 1 to 12, all amino acids having D 1 are D-types except compound 6, and hydroxy acids having A 1 are D-types. In said compounds 1 to 12, all amino acids except hydroxy acids having A 1 and amino acids having D 1 are L-types. In Table 1, C 6 H 5 -CH 2 - means benzyl, pF-C 6 H 4 -CH 2 - means p-fluorobenzyl, C 6 H 5 -CH 2 -O-C 6 H 4 -CH 2 - means benzyloxybenzyl, CH 3 -O-C 6 H 4 -CH 2 - means methoxybenzyl, C 6 H 5 -CH 2 -O-CH 2 - means benzyloxymethyl, c -C 6 H 11 -CH 2 - means cyclohexylmethyl and c -C 6 H 11 -CH 2 -O-C 6 H 4 -CH 2 - means cyclohexylmethyloxybenzyl, respectively. The amino acids in the context of this specification including said general formula (1) are abbreviated as follows. D -Hmp is 2(R)-hydroxy-3(R)-methylpentanoic acid, β HOMeVal is β-hydroxy-N-methylvaline, Cha is cyclohexylalanine, pFPhe is p-fluorophenylalanine, Ser(Bzl) is O-benzylserine, Tyr(Me) is O-methyltyrosine, Tyr(Bzl) is O-benzyltyrosine, and Tyr(c-C 6 H 11 -CH 2 -) is O-cyclohexylmethyltyrosine. The compound of this invention can be produced by the method of total synthesis described in Japanese Kokai Publication Hei-6-65291. Alternatively, the compound of the invention can also be produced by any semi-synthetic process using peptide fragments prepared from natural Aureobasidin by various chemical and/or enzymatic techniques. When the above-mentioned method of total synthesis or semi-synthesis is employed, the route of cyclizing a linear peptide of the following general formula (5) can be selected with advantage. For the preparation of the linear peptide described above, it is advantageous to synthesize 2 or 3 peptide fragments and link them together by condensation. The above-mentioned method of total synthesis for the compound of general formula (1) wherein A 1 stands for CH 3 CH 2 CH(CH 3 )-, B 1 for (CH 3 ) 2 CH-, C 1 for benzyl, D 1 for CH 3 -, E 1 for -(CH 2 ) 3 -, F 1 for CH 3 CH 2 CH(CH 3 )-, G 1 for (CH 3 ) 2 CH-, H 1 for (CH 3 ) 2 CHCH 2 -, I 1 for (CH 3 )C(OH)-; the hydroxy acid having A 1 is D-type, the amino acid having D 1 is D-type, and all the other amino acids are L-types, now described taking Compound 1 of the following general formula (6) as an example. The above-mentioned method of semi-synthesis is now described taking as an example Compound 9 of the following general formula (7) wherein C 1 represents cyclohexylmethyl, D 1 represents HOCH 2 -, and the other residues are identical to those of Compound 1. For the production of Compound 1 by total synthesis, the method comprises synthesizing the three fragment peptides of aIle 6 → MeVal 7 (fragment 1), Leu 8 → β HOMeVal 9 → D -Hmp 1 (fragment 2), and MeVal 2 → Phe 3 → D -MeAla 4 → Pro 5 (fragment 3), respectively, then condensing fragment 2 and fragment 3 between D -Hmp 1 and MeVal 2 , and finally condensing the resulting fragment 2 - fragment 3 peptide and fragment 1 between MeVal 7 and Leu 8 to provide a linear peptide of the following formula (8). Then, a cyclization is conducted to provide the objective Compound 1 of the formula (6). The method of semi-synthesis for the production of Compound 9 typically comprises treating aureobasidin A of formula (4) with anhydrous hydrogen fluoride (HF) and, then, treating it with a prolyl endo-peptidase to prepare aIle 6 → MeVal 7 → Leu 8 → β HOMeVal 9 → D -Hmp 1 → MeVal 2 (fragment 4). In the above production process, the prolyl endopeptidase cleaves the peptide bond between Pro 5 and aIle 6 of the linear nonapeptide (H-Phe→ MePhe→ Pro → aIle → MeVal → Leu → β HOMeVal → D -Hmp→ MeVal-OH) prepared by the above treatment of Aureobasidin A with an acid, e.g. anhydrous hydrogen fluoride, to thereby provide fragment 4. Regarding the conditions of HF treatment, the reaction temperature that can be used is -10 to 50°C, preferably 10 to 30°C, and the reaction time is 10 minutes to 40 hours, preferably 30 minutes to 20 hours. The yield can be increased by controlling the reactant concentration or adding a scavenger such as anisole. The method of producing fragment 4 from said linear nonapeptide (H-Phe → MePhe→ Pro→ aIle → MeVal→ Leu→ β HOMeVal → D -Hmp→ MeVal-OH) is not limited to the above procedure employing a prolyl endo-peptidase but may be a process involving sequential elimination of amino acids from the N-terminus using an amino peptidase or by Edman degradation. However, the procedure employing a prolyl endo-peptidase is most advantageous. The prolyl endo-peptidase mentioned above can be prepared from the bovine brain or microorganisms such as Flavobacterium spp. In the production of fragment 4, a derivative of the terminal amino acid, such as the benzyloxycarbonyl derivative, of said linear nonapeptide (H-Phe→ MePhe→ Pro → aIle → MeVal→ Leu → β HOMeVal → D -Hmp→ MeVal-OH) can also be used as the substrate. The thus-prepared fragment 4 and synthetic Cha 3 → D -MeSer 4 → Pro 5 (fragment 5) are condensed between MeVal 2 and Cha 3 to prepare a linear depsipeptide of the following formula (9). Then, the cyclization is carried out to provide the objective Compound 9 of formula (7). Selection of the reactants and reagents for use and the conditions of reactions in the respective stages of the above method of total synthesis or semi-synthesis is very important for providing the objective peptide in good yield and high stereochemical purity. Formation of peptide bonds in various stages of the above total synthesis or semi-synthesis can be achieved by various processes such as (1) the process comprising activating the carboxyl group with a water-soluble carbodiimide and HOBt, (2) the process comprising activating the carboxyl group with diphenyl phosphorylazide (DPPA) in the form of a carbonylazide, (3) the process employing (benzotriazolyloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), and most desirably (4) the process employing bromotrispyrrolidinophosphonium hexafluorophosphate (PyBroP) and a base such as diisopropylethylamine (DIEA). For the formation of a peptide bond, the processes (1) to (3) are generally used but when a peptide bond is formed using an N-methylamino acid as the amine component by such methods, the problems of low yield and racemization are often encountered. However, the above process (4) provides the objective peptide in high yield, avoiding the above problems. The ester bond between β HOMeVal 9 and D -Hmp 1 in said total synthesis can be formed by, for example, (5) the process employing PyBroP, (6) the process employing 2,4,6-trichlorobenzoyl chloride and involving a mixed anhydride with β HOMeVal, or preferably (7) the process employing dicyclohexylcarbodiimide (DCC) in combination with a catalyst such as dimethylaminopyridine (DMAP) or 4-pyrrolidinopyridine. By the last-mentioned process, the objective compound can be obtained in good yield. In practicing these processes, the hydroxyl group of β HOMeVal 9 may be free or previously protected. The condensation of fragment 2 and fragment 3 by peptide bond formation between D -Hmp 1 and MeVal 2 for the synthesis of Compound 1 can be carried out by any of the above processes (1) to (4) but is preferably carried out by process (4) employing PyBroP and a base. By this process, a fragment 2-fragment 3 peptide of high stereochemical purity can be obtained quickly and in good yield. In the synthesis of Compound 1, where the fragment 2 - fragment 3 peptide (Leu 8 → β HOMeVal 9 → D -Hmp 1 → MeVal 2 → Phe 3 → D -MeAla 4 → Pro 5 ) and fragment 1 (aIle 8 → MeVal 7 ) are condensed between Leu 8 and MeVal 7 or in the synthesis of Compound 9 where fragment 4 and fragment 5 are condensed by peptide bond formation between MeVal 2 and Phe 3 , the process employing PyBroP in combination with a base such as DIEA, for instance, can be utilized. However, the preferred process comprises activating the C-terminal carboxyl group with N-ethyl-N'-dimethylaminopropylcarbodiimide (EDC) and 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt). In order that the objective compound of high stereochemical purity may be produced, control of the reaction temperature is important. Generally, the reaction is conducted at -20 to 30°C. The cyclization in the final stage is carried out by the method which comprises using a linear peptide of the above formula (8) or (9) such that the C-terminal and N-terminal protective groups of the fragment 1 - fragment 2 - fragment 3 peptide or fragment 4 - fragment 5 peptide obtained in the preceding step have been removed beforehand, transforming said linear peptide to a peptide having an activated C-terminal carboxyl group and a free N-terminal amino acid, and reacting the transformed peptide in the presence of a base. The reaction temperature for this cyclization depends on the activated carboxyl group chosen but is generally in the range of -20 to 60°C and preferably -10 to 30°C. The reaction time for cyclization is several minutes to a few days, preferably a few hours to 24 hours. In the cyclization procedure described above, activation of the C-terminal carboxyl group can be achieved by conversion to an N-hydroxysuccinimide ester (ONSu) or the activating process using PyBroP. The base that can be used includes but is not limited to DIEA and pyridine. Referring to the case in which the C-terminal carboxyl group is activated in the form of ONSu, the ONSu ester can be obtained by reacting the linear peptide having a protected N-terminal amino group and a free C-terminal carboxyl group with the hydrochloride of a water-soluble carbodiimide (e.g.EDC) and N-hydroxysuccinimide (HONSu) in an organic solvent such as dimethylformamide (DMF), among other solvents, at -10 to 30°C. The N-terminus of the resulting linear peptide having the C-terminal ONSu active group can be converted to a free amino group or a salt thereof by a deprotection procedure suited to the N-terminal protecting group. As the cyclization proceeds in the presence of a base, the peptide of formula (8) or (9) wherein the C-terminus is a carboxyl group activated in the form of ONSu results ultimately. When the C-terminal carboxyl group is activated with PyBroP, the compound having an activated C-terminal carboxyl group can be obtained by reacting the peptide of formula (8) or (9) having a free N-terminal amino group or a salt thereof and a free C-terminal carboxyl group with PyBroP in the presence of a base, for example in an organic solvent such as methylene chloride, at a temperature of -10 to 30°C. In this case, the above reaction is accompanied by the cyclization reaction in parallel. In this cyclization, while the objective Compound 1 of formula (6) or Compound 9 of formula (7) can be obtained by whichever of the above-described two alternative procedures for activating the terminal carboxyl group, the yield of the reaction can be enhanced by meticulous control of reactant concentrations and reaction temperature and judicious selection of the solvent. In conducting the reaction in each of the above processes, protection of the N-terminal amino group can be carried out with, for example, t-butoxycarbonyl (Boc) and that of the C-terminal carboxyl group with Pac, Bzl and the like. If necessary, these protective groups can be removed by the corresponding deprotection procedures which are known or inferable from the prior art for transformation to the desired compound having a free N-terminal amino group or a salt thereof or a free C-terminal carboxyl group or a salt thereof. A large number of other protective groups are also known for the protection of a free carboxyl group or free amino group and can be utilized as well in the synthesis of the linear peptide of formula (8) or (9) and the synthesis of Compound 1 of formula (6) or Compound 9 of formula (7). Moreover, the hydroxyl group of β HOMeVal 9 may be protected, for example with Bzl or methyl, or with trimethylsilyl through a reaction with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). Even when the hydroxyl group of β HOMeVal 9 has been thus protected, the above cyclization reaction proceeds just as in the case of the unprotected hydroxy-compound to give the O-protected form of Compound 1 of formula (6) or Compound 9 of formula (7). After completion of the cyclization, the protective group can be removed by the corresponding deprotection procedure to provide Compound 1 of formula (6) or Compound 9 of formula (7). While the foregoing is a description of the synthetic technology for providing Compound 1 of formula (6) or Compound 9 of formula (7), the cyclic peptide of formula (1) according to this invention can be produced by the same procedures as those described for the synthesis of Compound 1 and Compound 9. Thus, the condensation by way of peptide bond formation can be carried out by any of the above described processes (1) through (4) and preferably by (4) the process employing PyBroP and a base, which provides the stereochemically pure objective compound quickly and in good yield. The condensation by way of an ester bond between the hydroxy acid residue having A 1 and the amino acid residue having I 1 can be carried out by any of the processes (5) to (7) described hereinbefore and preferably by (7) the process employing DCC in combination with a catalyst such as DMAP or 4-pyrrolidinopyridine, which provides the objective compound in good yield. The cyclization in the final stage can be carried out by converting the obtained linear depsipeptide to a peptide having an activated C-terminal carboxyl group and a free N-terminal amino group and reacting the converted peptide in the presence of a base. In this procedure, activation of the C-terminus can be carried out by the active ester involving the formation of ONSu or the activating process using PyBroP and, as the base mentioned above, DIEA, pyridine or the like can be employed. The protection of N-terminal, C-terminal and hydroxyl group in each steps of this reaction and their removal may be conducted as the same manner as the synthesis of compound 1 of formula (6) and compound 9 of formula (7). Thus the novel Aureobasidins whose minimum growth inhibitory concentration (MIC, µg/ml) against Cryptococcus and Aspergillus is very low and having no toxicological effect can be produced. For administration of the compound of this invention as a drug to man or other animals, it can be administered as it is or as formulated beforehand into a pharmaceutical composition containing 0.01 to 99.5%, preferably 0.5 to 90%, of the compound in a pharmaceutically acceptable, nontoxic and inert excipient. Said excipient may be, for example, one or more solid, semisolid or liquid diluents, fillers and/or other formulation auxiliaries. Such a pharmaceutical composition is preferably administered in unit dosage forms. Said pharmaceutical composition can be administered intravenously, orally, into tissues, topically (e.g. though the skin, etc.) or rectally. Of course, dosage forms suitable for the respective routes of administration should be employed. The dosage as an antifungal agent should preferably be selected according to the patient's age, body weight and other characteristics, the route of administration and the nature and severity of the disease. The generally recommended dosage to an adult human is 10 to 2000 mg/body/day. The required dosage may be somewhat less or more, depending on individual cases. The pharmaceutical composition may also be administered in 2 or 3 divided doses. For oral administration, either solid or liquid unit dosage forms, such as neat powders, powders, tablets, dragees, capsules, drops, sublingual, etc. can be provided. For non-oral administration, liquid unit dosage forms for subcutaneous, intramuscular or intravenous administration, such as solutions and suspensions, can be utilized. Thus, these preparations can be manufactured by suspending or dissolving a predetermined amount of the active compound in an injectable nontoxic liquid vehicle, such as an aqueous or oily medium, and sterilizing the resulting suspension or solution. For the local administration (e.g. through the skin, etc.), liquid, cream, powder, past, gel, ointment or other external application form can be utilized. Thus, these preparations can be manufactured by mixing the dose amount of the compound of this invention with one or more of flavor, colorant, filler, detergent, moisturelizer, skin softener, geller, vehicle, preservatives, stabilizer and the like acceptable for external application. For rectal administration, the compound of this invention can be used as a suppository formed mixing with the solid having a low melting point such as higher esters such as parmitic miristyl ester, polyethyleneglycol, cacao oil and mixture thereof. BEST MODE FOR IMPLEMENT THE INVENTION The following examples are intended to describe this invention in further detail and should by no means be interpreted as defining the scope of the invention. Example 1 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro) (Compound 1) a) Boc- D -MeAla-OH To 48 ml of a solution of Boc- D -Ala-OH (3.0 g, 15.9 mmol) in tetrahydrofuran (THF) was added 60% sodium hydride (1.9 g, 47.6 mmol) under ice-cooling and the mixture was stirred for 10 minutes. Then, methyl iodide (7.9 ml, 127 mmol) was added and the mixture was further stirred at room temperature for 22 hours. The reaction mixture was then concentrated under reduced pressure, ice-cooled, acidified with 10% citric acid-H 2 O, and extracted with ethyl acetate. The extract was washed with saturated NaCl-H 2 O, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane and the crystal crop was washed with hexane to provide the title compound. Yield 3.07 g (94.8%). b) Boc- D -MeAla- L -Pro-OPac In methylene chloride (12 ml) was dissolved Boc- D -MeAla-OH (1.50 g, 7.38 mmol) as well as HCl · H- L -Pro-OPac (1.53 g, 5.68 mmol) followed by addition PyBroP (3.44 g, 7.38 mmol) and DIEA (3.96 ml, 22.7 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 3 hours. This reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by medium-pressure silica gel column chromatography (silica gel 200 g, eluted with chloroform and chloroform-methanol 100:1). The eluate was concentrated under reduced pressure and crystallized from hexane and the crystal crop was washed with hexane to provide the title compound. Yield 1.90 g (78.0%). c) HCl · H- D -MeAla- L -Pro-OPac To Boc- D -MeAla- L -Pro-OPac (1.7 g, 4.06 mmol) was added 4.0N HCl/dioxane (30ml) and the mixture was allowed to stand at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, crystallized from ether, and washed with ether to provide the title compound. Yield 1.38 g (95.8%). d) Boc- L -Phe- D -MeAla- L -Pro-OPac To a solution of Boc- L -Phe-OH (1.26 g, 4.76 mmol) and HCl · H- D -MeAla- L -Pro-OPac (1.30 g, 3.66 mmol) in methylene chloride (10 ml) was added PyBroP (2.22 g, 4.76 mmol) as well as DIEA (2.55 ml, 14.6 mmol) under ice-cooling and the mixture was stirred under ice-cooling for 2 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was then purified by medium-pressure silica gel column chromatography (silica gel 200 g, eluted with toluene-ethyl acetate = 3:1 and 1:1) to provide the title compound. Yield 1.76 g (84.9%). e) HCl · H- L -Phe- D -MeAla- L -Pro-OPac To Boc- L -Phe- D -MeAla- L -Pro-OPac (1.70 g, 3.01 mmol) was added 4.0 N-hydrogen chloride/dioxane (30 ml)and the mixture was allowed to stand at room temperature for 30 minutes. This reaction mixture was concentrated under reduced pressure and the residue was crystallized from ether and washed with ether to provide the title compound. Yield 1.63 g (100%). f) Boc- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac To a solution of Boc- L -MeVal-OH (898 mg, 3.88 mmol) in methylene chloride (9 ml) was added HCl · H- L -Phe- D -MeAla- L -Pro-OPac (1.45g, 2.99mmol) as well as PyBroP (1.81g, 3.88mmol) under ice-cooling. Then, after addition of DIEA (2.08 ml, 12.0 mmol), the mixture was stirred under ice-cooling for 16 hours. This reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by medium-pressure silica gel column chromatography (silica gel 200 g, eluted with toluene-ethyl acetate = 2:1 and 1:1) to provide the title compound. Yield 1.67g (82.3%). g) HCl · H- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac To Boc- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac (1.00 g, 1.47 mmol) was added 4.0N-HCl/dioxane (18.4 ml) and the mixture was allowed to stand at room temperature for 50 minutes. This reaction mixture was concentrated under reduced pressure, crystallized from ether, and washed with ether to provide the title compound. Yield 838 mg(92.7%). h) Boc- DL -β HOMeVal-OBzl To a suspension of H- DL -β HOMeVal-OH (38.6 mg, 0.264 mmol) in DMF (0.57 ml) was added BSTFA (0.56 ml, 2.11 mmol) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added di-t-butyl-dicarbonate (72.8 µl, 0.317 mmol) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. This reaction mixture was concentrated under reduced pressure, diluted with 10% citric acid-H 2 O, and washed with saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The residual oil was dissolved in ethyl acetate (0.5 ml), followed by addition of triethylamine (55.0µ l, 0.396 mmol) and benzyl bromide (62.8 µ l, 0.528 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 5 minutes and, then, at room temperature for 48 hours. The reaction mixture was then concentrated under reduced pressure and purified by preparative silica gel thin layer chromatography (developed with chloroform-methanol = 19:1) to provide the title compound. Yield 60.7 mg (68.1%). i) HCl- DL -β HOMeVal-OBzl To Boc- DL -β HOMeVal-OBzl (472 mg, 1.40 mmol) was added 5.5N HCl/dioxane (29.5 ml) and the mixture was allowed to stand at room temperature for 1.5 hours. This reaction mixture was concentrated under reduced pressure, crystallized from ether, and washed with ether to provide the title compound. Yield 367 mg (95.7%). j) Boc- L -Leu- DL -β HOMeVal-OBzl To a solution of Boc- L -Leu-OH · H 2 O (1.34 g, 5.39 mmol) in methylene chloride (10 ml) was added HCl · H- DL -β HOMeVal-OBzl (981.1 mg, 3.59 mmol) as well as PyBroP (2.52 g, 5.39 mmol) under ice-cooling, followed by addition of DIEA (2.50 ml, 14.4 mmol), and the mixture was stirred under ice-cooling for 1 hour and, then, at room temperature for 8 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by medium-pressure silica gel column chromatography (silica gel 40 g, eluted with toluene-ethyl acetate = 3:1). The eluate was concentrated under reduced pressure and crystallized from hexane to provide the title compound. Yield 1.05 g (65.2%). k) Boc- L -Leu- DL -β HOMeVal-OH To a solution of Boc- L -Leu- DL -β HOMeVal-OBzl (43.5 mg, 96.5 µ mol) in methanol (40 ml) was added palladium black (40 mg) and, then, hydrogen gas was bubbled through the solution at room temperature for 50 minutes. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure to provide the title compound. Yield 30.6 mg (87.9%). 1) Boc- L -Leu- L -β HOMeVal- D -Hmp-OPac In THF (4.3 ml) was dissolved Boc- L -Leu- DL -β HOMeVal-OH (744 mg, 2.15 mmol) as well as phenacyl 2(R)-hydroxy-3(R)methylpentanoate ( D -Hmp-OPac) (589 mg, 2.36 mmol) and 4-pyrrolidinopyridine (95.6 mg, 0.65 mmol), followed by addition of DCC (487 mg, 2.36 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour, after which it was allowed to warm up to room temperature and stirred for 18 hours. This reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium-pressure silica gel column chromatography (silica gel 80 g, eluted with toluene-ethyl acetate = 5:1) to provide Boc- L -Leu- DL -β HOMeVal- D -Hmp-OPac (yield 1.00 g, 78.7%). This compound was further subjected to medium-pressure silica gel column chromatography (silica gel 200 g, eluted with toluene-ethyl acetate = 15:1 and 10:1) for fractionation of diastereomers to provide the title compound. Yield 357 mg (56.2%, based on the L-L isomer of Boc- L -Leu- DL -β HOMeVal-OH). m) Boc- L -Leu- L -β HOMeVal- D -Hmp-OH In 90% acetic acid/water (18.5 ml) was dissolved Boc- L -Leu- L -β HOMeVal- D -Hmp-OPac (220 mg, 0.37 mmol) followed by addition of zinc dust (3.60 g, 55.5 mmol) under ice-cooling and ultrasonic agitation. The mixture was further stirred by sonication under ice-cooling for 7.5 hours. The insoluble matter was then filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with 10% citric acid-water and extracted with ethyl acetate. The extract was washed with saturated sodium chloride-H 2 O, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by medium-pressure silica gel column chromatography (silica gel 10 g, eluted with chloroform-methanol-acetic acid = 50:1:0.5) to provide the title compound. Yield 133 mg (73.7%). n) HCl · H- L -MeVal-OPac To a solution of Boc- L -MeVal-OH (4.94 g, 21.4 mmol) in acetone (50 ml) was added triethylamine (3.30 ml, 23.8 mmol) as well as phenacyl bromide (4.77 g, 24.0 mmol) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour and further at room temperature for 2 hours. This reaction mixture was concentrated, diluted with ethyl acetate, and washed serially with water, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. To the residue was added 5.5N HCl/dioxane (77.8 ml, 0.428 mmol) and the mixture was allowed to stand at room temperature for 30 minutes. This reaction mixture was concentrated under reduced pressure, crystallized from ether and washed with ether to provide the title compound. Yield 6.08 g (99.3%). o) Boc- L -aIle- L -MeVal-OPac In methylene chloride (10 ml) was dissolved HCl · H- L -MeVal-Opac (1.12 g, 4.18 mmol) followed by addition of Boc- L -aIle-OH (1.06 g, 4.59 mmol) as well as PyBroP (2.57 g, 5.49 mmol) and DIEA (2.65 ml, 15.2mmol) under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 17 hours. This reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed serially with saturated sodium carbonate-H 2 O, saturated sodium chloride-H 2 O, 10% citric acid-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by medium-pressure silica gel column chromatography (silica gel 80 g, eluted with chloroform) to provide the title compound. Yield 764 mg (36.0%). p) Boc- L -aIle- L -MeVal-OH In 90% acetic acid/water (70 ml) was dissolved Boc- L -aIle- L -MeVal-OPac (657 mg, 1.42 mmol), followed by addition of zinc dust (4.64 g, 71.0 mmol) under ice-cooling and ultrasonic agitation for 7.5 hours. The insoluble matter was then filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed serially with 10% citric acid-H 2 O and saturated sodium chloride H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane and washed with hexane to provide the title compound. Yield 325 mg (66.5%). q) Boc- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac To a solution of Boc- L -Leu- L -β HOMeVal- D -Hmp-OH (60.0 mg, 0.123 mmol) in methylene chloride (400µ l) was added HCl · H- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac (114 mg, 0.184 mmol) as well as PyBroP (74.6 mg, 0.16 mmol) under ice-cooling, followed by addition of DIEA (86.0 µl, 0.491 mmol). The mixture was stirred under ice-cooling for 2 hours and then at room temperature for 13 hours. This reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by medium-pressure silica gel column chromatography (silica gel 20 g, eluted with toluene-ethyl acetate = 2:1 and 3:2) to provide the title compound. Yield 97.4 mg (75.5%). r) HCl · H- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac To Boc- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac (85 mg, 81.0 µmol) was added trifluoroacetic acid (500 µl, 6.48 mmol) under ice-cooling and the mixture was allowed to stand under ice-cooling for 30 minutes. This reaction mixture was concentrated under reduced pressure and, after addition of ether, 4.0 N HCl/dioxane (41 µl, 162 µmol) was added under ice-cooling. The mixture was allowed to stand at room temperature for 30 minutes. The resulting crystals were washed with ether to provide the title compound. Yield 59.2 mg (74.2%). s ) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac In DMF(200 µl) was dissolved Boc- L -aIle- L -MeVal-OH(29.0mg, 83.7 µmol) and HCl · "H- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac (55.0 mg, 55.8 µmol), and after HOOBt (11.0 mg, 67.0 µmol) was added under ice-cooling, a water-soluble carbodiimide (12.9 µl, 72.5 µmol) was added. The mixture was stirred under ice-cooling for 2 hours. The mixture was further stirred at room temperature for 17 hours, after which it was diluted with ethyl acetate and washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodium hydrogen carbonate-H 2 O, and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by preparative silica gel thin layer chromatography (developed with benzene-acetone = 3:1 and eluted with ethyl acetate) to provide the title compound. Yield 60.6 mg (85.1%). t) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OH In 90% acetic acid-water (2.0 ml) was dissolved Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OPac (50.0 mg, 39.2 µmol) followed by addition of zinc dust (513 mg, 7.84 mmol) under ice-cooling and the mixture was subjected to ultrasonic agitation under ice-cooling for 1 hour. The insoluble matter was filtered off and the filtrate was concentrated under reduced pressure and the residue was diluted with 10% citric acid-water and extracted with ethyl acetate. The extract was washed with saturated sodium chloride-H 2 O, dried over magnesium sulfate, and concentrated under reduced pressure to provide the title compound. Yield 48.3 mg. u) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OH To Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAIa- L -Pro-OH (48.3 mg, 39.2µ mol) was added trifluoroacetic acid (604µ l, 7.84 mmol) under ice-cooling and the mixture was allowed to stand under ice-cooling for 30 minutes. This reaction mixture was concentrated under reduced pressure and, after addition of ether, 4.0 N HCl/dioxane (29.5 µ l, 118µ mol) was added under ice-cooling. The mixture was allowed to stand under ice-cooling for 30 minutes. The resulting crystals were washed with ether to provide the title compound. Yield 33.3 mg (78.7%). v) Cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro) (Compound 1) In methylene chloride (11 ml) was dissolved HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeAla- L -Pro-OH (23.0 mg, 21.3µ mol) as well as DIEA (7.4 µ l, 42.6 µ mol) and this solution was added dropwise to a solution of PyBroP (49.4 mg, 106 µ mol) and DIEA (18.6 µ l, 106µ mol) in methylene chloride (11 ml) at room temperature over a period of 4 hours. The mixture was further stirred at room temperature for 20 hours. This reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed serially with 10% citric acid-H 2 O, saturated sodium chloride-H 2 O, saturated sodiumhydrogen carbonate-H 2 O and saturated sodium chloride-H 2 O. The washed solution was dried over magnesium sulfate and concentrated under reduced pressure and the residue was purified by preparative silica gel thin layer chromatography (developed and eluted with chloroform-methanol = 19:1) to provide the title compound. Yield 12.1 mg (55.5%).Physiochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.62, 7.95, 7.67 (total 3H, NH), 7.35-7.11 (total 5H, aromatic H), 5.79, 5.44-5.22, 4.97, 4.88, 4.73-4.56, 4.30, 4.04, 3.44 (total 10H), 3.33, 3.32, 3.20, 2.85 (total 12H, NCH 3 ), 1.09-0.71 (CH 3 ), and others. Example 2 Synthesis of cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeVal- L -Pro) (Compound 2) a) H- L -Phe- L -MePhe- L -Pro- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH(opening the ring of Aureobasidin A by HF) Anhydrous hydrogen fluoride (200 ml) was added into Aureobasidin A (6.0 g, 5.45 mmol) in cooling bath of dry ice-methanol, and then stirred at room temperature for 1.5 hours. After hydrogen fluoride was distilled off under reduced pressure, residue was lyophilized from dioxane. This was purified by high performance liquid chromatography (column: Soken Pack C-18, 60 x 500mm, eluted by 50 to 100 % of acetonitrile/0.05% aq. TFA) to provide the title compound. Yield 1.81 g (29.7 %). b) Z- L -Phe- L -MePhe- L -Pro- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH(wherein Z represents benzyloxycarbonyl) To dispersion of H- L -Phe- L -MePhe- L -Pro- L -aIle- L -MeVal - L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (200 mg, 0.179 mmol) in DMF (3.6 ml), triethylamine (50.2 µ l, 0.358 mmol) and benzyloxycarbonylsuccineimide (53.5 mg, 0.215 mmol) were added and stirred under ice-cooling for 1.5 hours. After concentrated under reduced pressure, precipitate was filtered out by addition of ethyl acetate and washed by 10 % citric acid-H 2 O and saturated sodium chloride-H 2 0. After dried over magnesium sulfate, concentrated under reduced pressure and the residue was purified by medium pressure silica gel column chromatography (eluted by chloroform-methanol-acetic acid 100: 2:2) to provide the title compound. Yield 183 mg (81.5 %). c) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH Z- L -Phe- L -MePhe- L -Pro- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (100 mg, 79.8 mmol) (wherein Z represents benzyloxycarbonyl) in ethanol (10 ml) was added to 50 mM potassium-phosphate buffer (pH 7.0, 89 ml). After stood at 30°C for 10 minutes, 50mM potassium-phosphate buffer (pH 7.0, 1.2 ml) in which prolylendopeptidase (Seikagakukogyo) (600 unit) was added and stirred for 72 hours, precipitate was removed by centrifugation (at 700 r.p.m. for 10 minutes) and the supernatant was concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (column:YMC C-18ODS, eluted by 30 to 90 % acetonitrile/0.05% aq. TFA) to provide the title compound. Yield 59.1mg (100 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH To HCl · H- L -aIle- L -MeVal- L -Leu- L -β HomeVal- D -Hmp- L -MeVal-OH (57.7mg, 81.0 µmol) in dioxan/water (2:1) were added triethylamine (14.6 µl, 105 µmol) and di-t-butyl-dicarbonate (24.0 µl, 105 µmol) and stirred for 3.5 hours at room temperature. After concentrated under reduced pressure, ethyl acetate was added and the mixture was washed by 10 % citric acid-H 2 O and saturated sodium chloride-H 2 0. After dried over magnesium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified by preparative silica gel thin layer chromatography (developed with chloroform-methanole:acetic acid 100:1:2, extracted with chloroform:methanol 10:1) to provide the title compound. Yield 51.2mg (77.8 %). e) Boc- D -MeVal-OH The title compound was obtained as the same manner as Example 1 a) using Boc- D -Val-OH (2.0 g, 9.21 mmol), 60 % sodium hydride (1.1 g, 27.6 mmol) and methyl iodide (4.56 ml, 73.6 mmol). Yield 1.54 g (72.5 % ). f) Boc- D -MeVal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 b) using Boc- D -MeVal-OH (300 mg, 1.30 mmol), HCl · H- L -Pro-OPac (291 mg, 1.08 mmol), PyBroP (606 mg, 1.30 mmol) and DIEA (753 µl, 4.32 mmol). Yield 372 mg (77.2 %). g) HCl · H- D -MeVal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 c) using Boc- D -MeVal- L -Pro-OPac(350 mg, 0.784 mmol) in 4.0 N hydrogen chloride/dioxane (5.88 ml). Yield 292 mg (97.3 %). h) Boc- L -Phe- D -VeBal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Phe-OH (180 mg, 0.679 mmol), HCl · H- D -MeVal- L -Pro-OPac (200 mg, 0.522 mmol), PyBroP (317 mg, 0.679 mmol) and DIEA (364 µl, 2.09 mmol). Yield 281 mg(90.7 %). i) HCl · H- L -Phe- D -VeBal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Phe- D -VeBal- L -Pro-OPac (190 mg, 0.320 mmol) in 4.0 N hydrogen chloride/dioxane (4.2 ml). Yield 169 mg (99.4 %). j) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeVal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- D -β HOMeVal- D -Hmp- L -MeVal-OH (35.0mg, 43.1 µmol), HCl · H- L -Phe- D -MeVal- L -Pro-OPac (34.2 mg, 64.6 µmol), HOOBt (8.7 mg, 64.6 µmol) and water soluble carbodiimide (11.4 µl, 64.6 µmol). Yield 34.6 mg (62.3 %) k) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeVal- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeVal- L -Pro-Oac (31.0 mg, 24.1 µmol), 90% acetic acid/water (1.2ml), zinc dust (313mg, 4.82 mmol). Yield 30.0 mg. l) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeVal- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -Meval- L -Phe- D -Meval- L -Pro-OH (30.0 mg, 25.7 µmol), trifluoroacetic acid (396 µl, 5.14 mmol) in 4.0 N hydrogen chloride/dioxane (12.9 µl, 51.4 µmol). Yield 19.6mg(73.6%). m) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeVal- L -Pro) (Compound 2) The title compound was obtained as the same manner as Example 1 v) using a solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Phe- D -MeVal- L -Pro-OH (15.0 mg, 13.6 µmol), DIEA (4.7 µl, 27.2 µmol) in methylene chloride (6.8 ml), and a solution of PyBroP (31.7 mg, 67.9 µmol) and DIEA (11.8 µl, 67.9 µmol) in methylene chloride (6.8 ml). Yield 5.0 mg (35.0 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz): δ 8.78, 8.10, 7.48 (total 3H, NH), 7.35-7.09 (total 5H, aromatic H), 5.78, 5.39, 5.20, 4.98-4.94, 4.80, 4.53, 4.37-4.31, 4.13, 3.45 (total 10H), 3.33, 3.22, 2.78 (total 12H, NCH 3 ), 1.11-0.70 (CH 3 ), and others. Example 3 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeAla- L -Pro) (Compound 3) a) Boc- L -Cha- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Cha-OH (137 mg, 0.507 mmol), HCl · H- D -MeAla- L -Pro-OPac (150 mg, 0.423 mmol), PyBroP (236 mg, 0.507 mmol) and DIEA (258 µl, 1.48 mmol). Yield 198 mg (82.1 %). b) HCl · H- L -Cha- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Cha- D -MeAla- L -Pro-OPac (180 mg, 0.315 mmol) and 4.0 N hydrogen chloride/dioxane (3.15 ml). Yield 148 mg (93.1 %). c) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (35.0 mg, 43.1 µmol), HCl · H- L -Cha- D -MeAla- L -Pro-OPac (32.8 mg, 64.6 µmol), HOOBt (8.7 mg, 64.6 µl) and water soluble carbodiimide (11.4 µl, 64.6 µmol). Yield 48.6 mg (89.2 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeAla- L -Pro-OPac (45.4 mg, 35.8 µmol), 90 % acetic acid/water (1.6 ml) and zinc dust (466 mg, 7.16 mmol). Yield 46.0 mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -Meval- L -Leu- L -β HOMeVal- D -Hmp- L -Meval- L -Cha- D -MeAla- L -Pro-OH (42.5 mg, 37.0 µmol), trifluoroacetic acid (570 µl, 7.40 mmol) and 4.0 N hydrogen chloride/dioxane (18.5 µl, 74.0 µmol). Yield 31.7mg (90.3%). f) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeAla- L -Pro) (Compound 3) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeAla- L -Pro-OH (25.0 mg, 21.1 µmol) and DIEA (7.3 µl, 42.2 µmol) in methylene chloride (10.6 ml), and solution of PyBroP (49.2 mg, 105.5 µmol) and DIEA (18.4 µl, 105.5 µmol) in methylene chloride (10.6 ml). Yield 6.8 mg (28.6 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.62, 8.55, 7.92, 7.87, 7.75 (total 3H, NH), 5.82, 5.44-5.20, 5.02-4.86, 4.67, 4,56, 4.20, 4.03, 3.37 (total 10H), 3.29, 3.28, 3.27, 3.25, 3.24 (total 12H, NCH 3 ), 1.03-0.76 (CH 3 ), and others. Example 4 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -pFPhe- D -MeAla- L -Pro) (Compound 4) a) Boc- L -pFPhe- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -pFPhe-OH (100 mg, 0.353 mmol), HCl · H- D -MeAla- L -Pro-OPac (105 mg, 0.294 mmol), PyBroP (165 mg, 0.353 mmol) and DIEA (179 µl, 1.03 mmol). Yield 153 mg(89.2 %). b) HCl · H- L -pFPhe- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -pFPhe- D -MeAla- L -Pro-OPac (140 mg, 0.240 mmol) and 4.0 N hydrogen chloride/dioxane (2.4 ml). Yield 120 mg (96.8 %). c) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -pFPhe- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- D -β HOMeVal- D -Hmp- L -MeVal-OH (35.0 mg, 43.1 µmol), HCl · H- L -pFPhe- D -MeAla- L -Pro-OPac (33.6mg, 64.6 µmol), HOOBt (8.7 mg, 64.6 µmol) and water soluble carbodiimide (11.4 µl, 64.6 µmol). Yield 48.8 mg (88.7 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -pFPhe- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -pFPhe- D -MeAla- L -Pro-OPac (45.3 mg, 35.4 µmol), 90 % acetic acid/water (1.7 ml) and zinc dust (920 mg, 14.1 mmol). Yield 47.2mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -pFPhe- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -PFPhe- D -MeAla- L -Pro-OH (44.0 mg, 37.9 µmol), trifluoroacetic acid (584 µl, 7.58 mmol) and 4.0 N hydrogen chloride/dioxane (18.9 µl, 75.8 µmol). Yield 34.9 mg (96.1 %). f) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -pFPhe- D -MeAla- L -Pro) (Compound 4) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -PFPhe- D -MeAla- L -Pro-OH (28.0 mg, 25.5 µmol) and DIEA (8.9 µl, 51.1 µmol) in methylene chloride (12.8 ml), and solution of PyBroP (59.4 mg, 128 µmol) and DIEA (22.2 µl, 128 µmol) in methylene chloride(12.8 ml). Yield 7.94 mg (29.8 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.65, 7.98, 7.66 (total 3H, NH), 7.09-7.05 (total 4H, aromatic H), 5.84, 5.31, 5.19, 4.97, 4.88, 4.73-4.57, 4.17, 4.04, 3.44 (total 10H), 3.33, 3.32, 3.19, 2.94 (total 12H, NCH 3 ), 1.07-0.73 (CH 3 ), and others. Example 5 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro) (Compound 5) a) Boc- L -Leu- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Leu-OH · H 2 O (91.4 mg, 0.367 mmol), HCl · H- D -MeAla- L -Pro-OPac (100 mg, 0.282 mmol), PyBroP (171 mg, 0.367 mmol) and DIEA (197 µl, 1.13 mmol). Yield 124 mg (82.7 %). b) HCl · H- L -Leu- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Leu- D -MeAla- L -Pro-OPac (100 mg, 0.188 mmol) and 4.0 N hydrogen chloride/dioxane (1.88 ml). Yield 80.4 mg (91.4 %). c) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (40.0 mg, 49.2 µmol), HCl · H- L -Leu- D -MeAla- L -Pro-OPac (34.6 mg, 73.8 mmol), HOOBt (12.0mg, 73.8 µl) and water soluble carbodiimide (13.1 µl, 73.8 µmol). Yield 33.5 mg (55.5 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro-OPac (30.0 mg, 24.4 µmol), 90 % acetic acid/water (1.5ml) and zinc dust (350mg, 4.88 mmol). Yield 25.1 mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro-OH (25.0 mg, 22.5 µmol), trifluoroacetic acid (347 µl, 4.50mmol) and 4.0 N hydrogen chloride/dioxane (8.5 µl, 33.8 µmol). Yield 21.2 mg (93.2 %). f) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro) (Compound 5) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Leu- D -MeAla- L -Pro-OH (19.0 mg, 18.2 µmol) and DIEA (6.3 µl, 36.4 µmol) in methylene chloride (9.1 ml), and solution of PyBroP (42.4 mg, 90.9 µmol) and DIEA (15.8 µl, 90.9 µmol) in methylene chloride (9.1 ml). Yield 7.1 mg (39.4 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.60, 8.53, 7.88, 7.76, 7.69 (total 3H, NH), 5.77, 5.22, 4.98-4.80, 4.67, 4,56, 4.00 (total 11H), 3.38, 3.31, 3.29, 3.25, 3.24, 3.10 (total 12H, NCH 3 ), 1.16-0.76 (CH 3 ), and others. Example 6 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- L -MePhe- L -Pro) (Compound 6) a) Boc- L -Cha- L -MePhe- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Cha-OH (109 mg, 0.404 mmol), HCl · H- L -MePhe- L -Pro-OPac (150 mg, 0.336 mmol), PyBroP (188 mg, 0.404 mmol) and DIEA (205 µl, 1.18 mmol). Yield 201 mg (90.3 %). b) HCl · H- L -Cha- L -MePhe- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Cha- L -MePhe- L -Pro-OPac (180 mg, 0.272 mmol) and 4.0 N hydrogen chloride/dioxane (2.72 ml). Yield 103 mg (63.2 %). c) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- L -MePhe- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (40.0 mg, 49.2 µmol), HCl · H- L -Cha- L -MePhe- L -Pro-OPac (44.2 mg, 73.8 µmol), HOOBt (9.9 mg, 73.8 µl) and water soluble carbodiimide (13.0 µl, 73.8 µmol). Yield 45.9 mg (68.8 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- L -MePhe- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- L -MePhe- L -Pro-OPac (42.0 mg, 31.0 µmol), 90 % acetic acid/water (2.0 ml) and zinc dust (402 mg, 6.19 mmol). Yield 46.1 mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- L -MePhe- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -Meval- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- L -MePhe- L -Pro-OH (46.0 mg, 37.1 µmol), trifluoroacetic acid (570 µl, 7.42mmol) and 4.0 N hydrogen chloride/dioxane (14.0 µl, 55.7 µmol). Yield 43.5mg (100%). f) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -Meval- L -Cha- L -MePhe- L -Pro) (Compound 6) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- L -MePhe- L -Pro-OH (25.0 mg, 21.3 µmol) and DIEA (7.4 µl, 42.5 µmol) in methylene chloride (10.5 ml), and solution of PyBroP (49.7 mg, 106.5 µmol) and DIEA (18.5 µl, 106.5 µmol) in methylene chloride (10.5 ml). Yield 5.7 mg (23.9 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.68, 7.95, 7.88, 7.62 (total 3H, NH), 7.32-7.29, 7.17-7.15 (total 5H, aromatic H), 5.79, 5.72, 5.34, 5.25-4.81, 4.51, 4.23, 3.98, 3.38 (total 11H), 3.29, 3.27, 3.25, 3.20, 3.16, 3.13 (total 12H, NCH 3 ), 1.08-0.80 (CH 3 ), and others. Example 7 Synthesis of cyclo(L-aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro) (Compound 7) a) Boc- L -Ser(Bzl)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Ser(Bzl)-OH (106 mg, 0.360 mmol), HCl · H- D -MeAla- L -Pro-OPac (106 mg, 0.300 mmol), PyBroP (209 mg, 0.450 mmol) and DIEA (209 µl, 1.20 mmol). Yield 163 mg (91.4 %). b) HCl · H- L -Ser(Bzl)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Ser(Bzl)- D -MeAla- L -Pro-OPac (150 mg, 0.252 mmol) and 4.0 N hydrogen chloride/dioxane (2.52 ml). Yield 128 mg (95.4 %). c) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (50.0 mg, 61.5 µmol), HCl · H- L -Ser(Bzl)- D -MeAla- L -Pro-OPac (49.0 mg, 92.2 µmol), HOOBt (12.5mg, 92.2 µmol) and water soluble carbodiimide (16.3 µl, 92.2 µmol). Yield 61.2 mg (77.1 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro-OPac (50.0 mg, 38.7 µmol), 90 % acetic acid/water (2.0 ml) and zinc dust (503 mg, 7.74 mmol). Yield 45.0 mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro-OH (43.0 mg, 36.7 µmol), trifluoroacetic acid (560 µl, 7.34mmol) and 4.0 N hydrogen chloride/dioxane (13.7 µl, 55.1 µmol). Yield 34.0 mg (82.8 %). f) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro) (Compound 7) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Ser(Bzl)- D -MeAla- L -Pro-OH (30.0mg, 27.1 µ mol) and DIEA (9.4µ l, 54.1 µ mol) in methylene chloride (13.5 ml), and solution of PyBroP (62.9 mg, 135.3 µ mol) and DIEA (23.5 µ l, 135µ mol) in methylene chloride (13.5 ml). Yield 12.9 mg (45.2 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.47, 7.86, 7.76 (total 3H, NH), 7.32, 7.30 (total 5H, aromatic H), 5.78, 5.46-5.40, 5.21, 5.06, 4.93, 4.72-4.48, 4.18, 4.05-3.94, 3.65, 3.46, 3.38 (total 15 H), 3.29, 3.27, 3.24, 3.23 (total 12H, NCH 3 ), 1.40-1.26, 0.99-0.77 (CH 3 ), and others. Example 8 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro) (Compound 8) a) Boc- L -Cha- D -MeVal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Cha-OH (74.0 mg, 0.272 mmol), HCl · H- D -MeVal- L -Pro-OPac (80.0mg, 0.209 mmol), PyBroP (127 mg, 0.272 mmol) and DIEA (146µ l, 0.836mmol). Yield 107 mg (85.6 %). b) HCl · H- L -Cha- D -MeVal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 u) using Boc- L -Cha- D -MeVal- L -Pro-OPac (100 mg, 0.167 mmol) trifluoroacetate (515 µ l, 6.68 mmol) and 4.0 N hydrogen chloride/dioxane (125µ l, 0.501 mmol). Yield 75.1mg (84.4 %). c) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (20.0 mg, 24.6µ mol), HCl · H- L -Cha- D -MeVal- L -Pro-OPac (19.8 mg, 37.0 µ mol), HOOBt (6.2 mg, 37.0 µ mol) and water soluble carbodiimide (6.6µ l, 37.0 µ mol). Yield 21.6mg (67.9 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro-OPac (36.2 mg, 27.9 µmol), 90 % acetic acid/water (1.4 ml) and zinc dust (366 mg, 5.60 mmol). Yield 40.7 mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro-OH (37.7 mg, 32.1 µmol), trifluoroacetic acid (494 µl, 6.41mmol) and 4.0 N hydrogen chloride/dioxane (12.0 µl, 48.1 µmol). Yield 24.8 mg (86.4 %). f) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro) (Compound 8) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeVal- L -Pro-OH (20.0 mg, 18.0 µmol) and DIEA (6.3 µl, 36.0 µmol) in methylene chloride(9.0 ml), and solution of PyBroP (42.0 mg, 89.9 µmol) and DIEA (15.7 µl, 89.9 µmol) in methylene chloride (9.0 ml). Yield 3.9 mg (20.5 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.70, 8.02, 7.57 (total 3H, NH), 5.80, 5.44, 5.29-5.06, 4.99-4.80, 4.49, 4.31, 4.25, 4.09, 3.38 (total 11H), 3.29, 3.28, 3.27, 3.25, 3.08 (total 12H, NCH 3 ), 1.06-0.76 (CH 3 ), and others. Example 9 Synthesis of cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer- L -Pro) (Compound 9) a) Boc- L -Cha- D -MeSer(Bzl)- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Cha-OH (99.6 mg, 0.365 mmol), HCl · H- D -MeSer(Bzl)- L -Pro-OPac (140 mg, 0.304 mmol), PyBroP (142 mg, 0.456 mmol) and DIEA (212 µl, 1.22 mmol). Yield 166 mg (80.5 %). b) HCl · H- L -Cha- D -MeSer(Bzl)- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Cha- D -MeSer(Bzl)- L -Pro-OPac (160 mg, 0.235mmol) and 4.0N hydrogen chloride/dioxane (2.94ml). Yield 132 mg (91.0 %). c) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (60.0 mg, 73.8 µmol), HCl · H- L -Cha- D -MeSer(Bzl)- L -Pro-OPac (67.7 mg, 0.110 mmol), HOOBt (18.1mg, 0.110 mol) and water soluble carbodiimide (19.5 µl, 0.110 mmol). Yield 81.9 mg (80.7 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro-OPac (143 mg, 0.104 mmol), 90 % acetic acid/water (5.0 ml) and zinc dust (1.35 g, 20.8 mmol). Yield 123 mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro-OH(70.0mg, 55.7 µmol), trifluoroacetic acid (855 µl, 11.1mmol) and 4.0 N hydrogen chloride/dioxane (27.8 µl, 0.111 mmol). Yield 51.9 mg (78.0 %). f) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro-OH (48.0 mg, 40.2 µmol) and DIEA (14.0 µl, 80.5 µmol) in methylene chloride (20.1 ml), and solution of PyBroP (93.7 mg, 0.201 mmol) and DIEA (35.0 µl, 0.201 mmol) in methylene chloride (20.1 ml). Yield 15.7mg (34.3 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.55, 7.90, 7.68 (total 3H, NH), 7.32-7.26 (total 5H, aromatic H), 5.81, 5.43, 5.42, 5.27-5.19, 5.02-4.81, 4.68, 4.55, 4.21, 3.99, 3.88, 3.37 (total 13H), 3.30, 3.29, 3.26, 3.25, 3.23, 3.08 (total 12H, NCH 3 ), 1.03-0.76 (CH 3 ), and others. g) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer- L -Pro) (Compound 9) To cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Cha- D -MeSer(Bzl)- L -Pro)(11.6 mg, 10.2 µmol) in methanol(1.5ml) was added palladium black (15 mg), and hydrogen gas was blown in for 2 hours at room temperature, and an additional 1 hour at 30°C. After filtering out the catalyst and concentrating under reduced pressure, the residue was purified by preparative silica gel thin layer chromatography (developed and extracted with chloroform-methanol 19:1) to provide the title compound. Yield 8.6 mg (80.5 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.63, 8.56, 7.90, 7.76 (total 3H, NH), 5.81, 5.42, 5.28, 5.21, 4.98, 4.90, 4.70-4.56, 4.21, 4.10-4.03, 3.37 (total 13H), 3.39, 3.29, 3.26, 3.25, 3.23 (total 12H, NCH 3 ), 1.02-0.76 (CH 3 ), and others. Example 10 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro) (Compound 10) a) Boc- L -Tyr(Bzl)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Tyr(Bzl)-OH (680 mg, 1.83 mmol), HCl · H- D -MeAla- L -Pro-OPac (500 mg, 1.48 mmol), PyBroP (853 mg, 1.83 mmol) and DIEA (981 µl, 5.63 mmol). Yield 827 mg (87.4 %). b) HCl · H- L -Tyr(Bzl)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Tyr(Bzl)- D -MeAla- L -Pro-OPac (428 mg, 0.636 mmol) and 4.0 N hydrogen chloride/dioxane (6.36 ml). Yield 355 mg (91.6 %). c) Boc- L -aIle- L -Meval- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (100 mg, 0.123mmol), HCl · H- L -Tyr(Bzl)- D -MeAla- L -Pro-OPac (112 mg, 0.184 mmol), HOOBt (30.1mg, 0.184 mmol) and water soluble carbodiimide (32.7 µl, 0.184 mmol). Yield 125 mg (74.3 %). d) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro-OPac (85.0 mg, 62.1 µmol), 90 % acetic acid/water (3.0 ml) and dust powder (808 mg, 12.4 mmol). Yield 77.6 mg. e) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro-OH (77.6 mg, 62.1 µmol), trifluoroacetic acid (220 µl, 2.84mmol) and 4.0 N hydrogen chloride/dioxane (23.3 µl, 93.2 µmol). Yield 70.8 mg (96.1 %). f) cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro) (Compound 10) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro-OH (70.8 mg, 59.7 µmol) and DIEA (20.8 µl, 0.119 mmol) in methylene chloride (30.0 ml), and solution of PyBroP (139 mg, 0.298 mmol) and DIEA (52.0 µl, 0.298 mmol) in methylene chloride (30.0 ml). Yield 28.0mg (41.5 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.65, 8.02, 7.72 (total 3H, NH), 7.53-7.29, 7.03 (total 9H, aromatic H), 5.83, 5.32, 5.20-4.91, 4.69-4.57, 4.25, 4.04, 3.43 (total 13H), 3.32, 3.20, 2.97, 2.94 (total 12H, NCH 3 ), 1.08-0.74 (CH 3 ), and others. Example 11 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Me)- D -MeAla- L -Pro) (Compound 11) a) cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr- D -MeAla- L -Pro) To cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Bzl)- D -MeAla- L -Pro)(28.0 mg, 24.7 µmol) in methanol(30 ml) was added palladium black (15 mg), and hydrogen gas was blown in for 4 hours at room temperature. After filtering out the catalyst and concentrating under reduced pressure, the residue was purified by preparative silica gel thin layer chromatography (developed and extracted by chloroform-methanol 19:1) to provide the title compound. Yield 18.2 mg (90.6 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.52, 7.89, 7.56 (total 3H, NH), 6.86 (total 4H, aromatic H), 5.75, 5.40, 5.21, 5.02, 4.79, 4.75, 4.66, 4.54, 4.31, 4.06, 3.53 (total 11H), 3.37, 3.32, 3.23, 2.73 (total 12H, NCH 3 ), 1.07-0.69 (CH 3 ), and others. b) cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(Me)- D -MeAla- L -Pro) (Compound 11) To cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr- D -MeAla- L -Pro)(3.0 mg, 2.88µ mol) in methanol-acetonitrile (1:9) (100µ l) was added DIEA (0.7µ , 4.04 µ mol) and trimethylsilyldiazomethane (4.9µ l, 43.2 µ mol). The obtained mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developed and extracted by chloroform-methanol 19:1) to provide the title compound. Yield 2.1 mg (69.1 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.65, 8.04, 7.74 (total 3H, NH), 7.04, 6.90 (total 4H, aromatic H), 5.83, 5.31, 5.18, 4.94, 4.67, 4.60, 4.23, 4.04, 3.47, 3.41 (total 13H), 3.82 (3H, OCH 3 ), 3.32, 3.31, 3.20, 2.99 (total 12H, NCH 3 ), 1.07-0.75 (CH 3 ), and others. Example 12 Synthesis of cyclo( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro) (Compound 12) a) Boc- L -Tyr(c-C 6 H 11 -CH 2 -)-OH Under ice-cooling, 60 % sodium hydride (229 mg, 5.73 mmol) was added to Boc- L -Tyr-OH (500 mg, 2.29 mmol) in DMF(4.6 ml). The mixture was stirred for 1 hour under ice-cooling, then added cyclohexylmethyl bromide (317 µ l, 3.44 mmol). The resulting mixture was stirred for 5 hours under ice-cooling. After concentrating under reduced pressure, the residue was adjusted the pH to 4 with 10 % citric acid in water and extracted with ethyl acetate. The extract was washed with saturated sodium chloride-H 2 O, dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound. Yield 269mg(37.3 %). b) Boc- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 d) using Boc- L -Tyr(c-C 6 H 11 -CH 2 -)-OH (138 mg, 0.366 mmol), HCl · H- D -MeAla- L -Pro-OPac (100 mg, 0.282 mmol), PyBroP (171 mg, 0.366 mmol) and DIEA (197 µl, 1.13 mmol). Yield 136 mg (71.2 %). c) HCl · H- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 e) using Boc- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OPac (136 mg, 0.198 mmol) and 4.0 N hydrogen chloride/dioxane (1.98 ml). Yield 111 mg (90.0 %). d) Boc- L -aIle- L -MeVal- L -Leu- L - β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OPac The title compound was obtained as the same manner as Example 1 s) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal-OH (30.0 mg, 36.9 µmol), HCl · H- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OPac (33.9 mg, 55.3 µmol), HOOBt (9.0 mg, 55.3 µmol) and water soluble carbodiimide (9.8 µl, 55.3 µmol). Yield 46.2 mg (91.2 %). e) Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 t) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OPac (43.3 mg, 31.5 µmol), 90 % acetic acid/water (1.0 ml) and zinc dust (410 mg, 6.31 mmol). Yield 37.4 mg. f) HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OH The title compound was obtained as the same manner as Example 1 u) using Boc- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OH (37.4 mg, 29.8 µmol), trifluoroacetic acid (92.0 µl, 1.19mmol) and 4.0 N hydrogen chloride/dioxane (11.2 µl, 44.7 µmol). Yield 28.7 mg (80.8 %). g) cyclo ( L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro) (Compound 12) The title compound was obtained as the same manner as Example 1 v) using solution of HCl · H- L -aIle- L -MeVal- L -Leu- L -β HOMeVal- D -Hmp- L -MeVal- L -Tyr(c-C 6 H 11 -CH 2 -)- D -MeAla- L -Pro-OH (25.0 mg, 20.9 µmol) and DIEA (7.3 µl, 41.9 µlmol) in methylene chloride (10.5 ml), and solution of PyBroP (46.8 mg, 0.105 mmol) and DIEA (18.3 µl, 0.105 mmol) in methylene chloride (10.5 ml). Yield 12.5mg (52.3 %).The physicochemical properties of the title compound are shown below. 1 H-NMR (CDCl 3 , 270 MHz) :δ 8.70, 8.07, 7.78 (total 3H, NH), 7.05, 6.85 (total 4H, aromatic H), 5.85, 5.30, 5.18, 4.96, 4.68, 4.64, 4.58, 4.27, 4.04, 3.77, 3.42 (total 13H), 3.32, 3.18, 3.02 (total 12H, NCH 3 ), 1.07-0.75 (CH 3 ), and others. The elementary analysis, FABMS and amino acid analysis of the resulting compound 1 to 12 and their biological properties were as follows. (1) The results of the elementary analysis, FABMS and amino acid analysis The results of the elementary analysis, FABMS and amino acid analysis are shown in Table 2. The amino acid analysis was conducted using Nippondenshi JCL-300 and detected by ninhydrine reaction. Compound Number Molecular Formula Elementary Analysis(%) Found/Anal.Calcd FABMS Amino Acid Analysis C H N 1 C 54 H 88 N 8 O 11 62. 59 8.81 10.73 1025 (M+H), Pro, alle, 63.26 8.65 10.93 1047 (M+Na) Leu, Phe 2 C 56 H 92 N 8 O 11 61.93 9.08 10.18 1053 (M+H), Pro, alle, 63. 85 8.80 10.64 1075 (M+Na) Leu, Phe 3 C 54 H 94 N 8 O 11 61.91 9.28 10.39 1031 (M+H), Pro, alle, 62. 89 9.19 10.86 1053 (M+Na) Leu, Cha 4 C 54 H 87 N 8 O 11 F 64.38 8.19 10.01 1043 (M+H), Pro, alle, 62.17 8.40 10.74 1065 (M+Na) Leu, pFPhe 5 C 51 H 90 N 8 O 11 61.85 9.34 11.02 991 (M+H), Pro, alle, 61.79 9.15 11.30 1013 (M+Na) Leu 6 C 60 H 98 N 8 O 11 65.17 8.68 10.43 1107 (M+H), Pro, alle, 65.07 8.92 10.12 1129 (M+Na) Leu, Cha 7 C 55 H 90 N 8 O 12 62.39 8.83 10.46 1055 (M+H), Pro, alle, 62.60 8.60 10.62 1077 (M+Na) Leu, Ser 8 C 56 H 98 N 8 O 11 63.82 9.04 10.86 1059 (M+H), Pro, alle, 63.48 9.32 10.58 1081 (M+Na) Leu, Cha 9 C 54 H 94 N 8 O 12 62.31 8.86 10.91 1047 (M+H), Pro, alle, 61.93 9.05 10.70 1069 (M+Na) Leu, Cha 10 C 61 H 94 N 8 O 12 64.46 8.65 9.44 1131 (M+H), Pro, alle, 64.75 8.37 9.90 1153 (M+Na) Leu 11 C 55 H 90 N 8 O 12 62.97 8.51 10.75 1055 (M+H), Pro, alle, 62.60 8.60 10.62 1077 (M+Na) Leu 12 C 61 H 100 N 8 O 12 63.92 8.47 10.17 1137 (M+H), Pro, alle, 64.41 8.86 9.85 1159 (M+Na) Leu (2) Biological property Minimum growth inhibiting concentration (MIC,µ g/ml) against fungi of Compound 1 to 12 are shown in Table 3 and Table 4. MIC was measured by agarose plate dilution method (cultivated at 30°C for 2 days) using saburo-dextrose agarose culture (glucose 2W/V %, polipeptone 1W/V %, agarose 1.5 W/V %). Control was Aureobasidin A (AbA). M I C (µg/ml) Eumycetes Tested AbA Compound Number 1 2 3 4 5 Candida albicans TIMM0136 0.025 0.05 0.025 0.0125 0.10 0.10 Candida albicans TIMM0171 0.025 0.05 0.025 0.025 0.05 0.05 Candida kefyr TIMM0301 0.39 0.20 0.20 0.20 0.20 0.20 Candida glabrata TIMM1062 0.20 0.20 0.20 0.10 0.20 0.20 Cryptococcus neoformans TIMM0354 0.78 3.12 1.56 0.10 3.12 0.39 Aspergillus fumigatus TIMM2766 >25 12.5 6.25 3.12 12.5 25 Eumycetes Tested M I C (µg/ml) AbA Compound Number 6 7 8 9 10 11 12 Candida albicans TIMM0136 0.025 0.39 0.10 0.10 0.20 0.05 0.10 0.10 Candida albicans TIMM0171 0.025 0.20 0.05 0.05 0.20 0.05 0.10 0.39 Candida kefyr TIMM0301 0.39 1.56 0.78 0.78 0.78 0.78 0.39 1.56 Candida glabrata TIMM1062 0.20 1.56 0.78 0.78 0.78 1.56 0.39 0.39 Cryptococcus neoformans TIMM0354 0.78 0.20 0.39 0.39 0.20 0.78 0.78 0.20 Aspergillus fumigatus TIMM2766 >25 >25 >25 >25 >25 1.56 12.5 1.56 Compound 1 to 5, 10 to 12 had activity for Aspergillus at the concentration of 1.56 to 25 µ g/ml. For Cryptococcus , compound 3, 5 to 9 and 12 had activity at the concentration of 0.10 to 0.39µ g/ml. In particular, compound 3 and 12 had activity for Aspergillus at 3.12µ g/ml and 1.56 µ g/ml respectively, and also showed strong activity for Cryptococcus , having stronger activity than Aureobasidin A. Further, compound 1 to 12 was administered intraperitoneally to ICR mouse at a dose of 100mg/kg, but no toxicity was detected. From these biological properties, the compounds of this invention were found to be effective for treatment of many kinds of mycosis such as one caused by Cryptococcus , Aspergillus or the like. INDUSTRIAL APPLICABILITY The compound according to this invention has an excellent activity against not only Candida but also at least one of Cryptococcus and Aspergillus , thus has much effective applicability for antifungal agent having broader spectrum.

Claims: An Aureobasidin compound of general formula (1): wherein A 1 , B 1 , F 1 , G 1 and H 1 are the same or different each other and each represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms; C 1 represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, benzyloxymethyl, benzyl, a substituted benzyl, phenyl or a substituted phenyl (said substituted benzyl or substituted phenyl means benzyl or phenyl substituted by at least one substituent selected from a straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, benzyloxy and halogen); D 1 represents a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, hydroxymethyl or benzyl (where C 1 is benzyl o-flurobenzyl or m-flurobenzyl, D 1 is a group other than benzyl and hydroxymethyl); E 1 represents a straight-chain alkylene having 1 to 5 carbon atoms; I 1 represents a hydroxy-substituted lower alkyl having 1 to 6 carbon atoms. The Aureobasidin compound according to Claim 1, wherein; said A 1 is (CH 3 ) 2 CH- or CH 3 CH 2 CH(CH 3 )-, said B 1 is (CH 3 ) 2 CH-, said C 1 is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms, a cycloalkyl having 3 to 7 carbon atoms, benzyloxymethyl, benzyl, a substituted benzyl, phenyl or a substituted phenyl (said substituted benzyl or substituted phenyl means benzyl or phenyl substituted by at least one substituent selected from a straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, benzyloxy and halogen), said D 1 is a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, hydroxymethyl or benzyl (where C 1 is benzyl o-flurobenzyl or m-flurobenzyl, D 1 is not benzyl and hydroxymethyl), said E 1 is -(CH 2 ) 3 -, said F 1 is (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 - or CH 3 CH 2 CH(CH 3 )-, said G 1 is (CH 3 ) 2 CH-, said H 1 is (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 - or CH 3 CH 2 CH(CH 3 )-, and, said I 1 is (CH 3 ) 2 C(OH)-. The Aureobasidin compound according to Claim 2, wherein; said A 1 is (CH 3 ) 2 CH- or CH 3 CH 2 CH(CH 3 )-, said B 1 is (CH 3 ) 2 CH-, said C 1 is CH 3 -, (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 -, CH 3 CH 2 CH(CH 3 )-, cyclohexylmethyl, benzyloxymethyl, benzyl or a substituted benzyl (said substituted benzyl means benzyl or phenyl substituted by at least one substituent selected from a straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, cycloalkoxy having 3 to 7 carbon atoms, benzyloxy and halogen), said D 1 is CH 3 -, (CH 3 ) 2 CH 2 -, (CH 3 ) 2 CHCH 2 -, CH 3 CH,CH(CH 3 )-, hydroxymethyl or benzyl (where C 1 is benzyl o-flurobenzyl or m-flurobenzyl, D 1 is not benzyl and hydroxymethyl), said E 1 is -(CH 2 ) 3 -, said F 1 is (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 - or CH 3 CH 2 CH(CH 3 )-, said G 1 is (CH 3 ) 2 CH-, said H 1 is (CH 3 ) 2 CH-, (CH 3 ) 2 CHCH 2 - or CH 3 CH 2 CH(CH 3 )-, and, said I 1 is (CH 3 ) 2 C(OH)-. Aureobasidin compound as defined in any of claims 1 to 3 for use as a therapeutically active agent. Aureobasidin compound according to claim 4 for use in the therapy of fungal infections. Aureobasidin compound according to claim 5 for use in the therapy against Cryptococcus and/or Aspergillus . Pharmaceutical composition comprising an aureobasidin compound as defined in any of claims 1 to 3 and a pharmaceutically acceptable excipient. Use of a pharmaceutical composition as defined in claim 7 in the manufacture of a medicament for the therapy of fungal infections. Use according to claim 8 in the therapy against Cryptococcus and/or Aspergillus .

Inventors: INAMI KAORU, INOUE TETSUYA, KATO IKUNOSHIN, KUROME TORU, TAKESAKO KAZUTOH, INAMI, KAORU, INOUE, TETSUYA, KATO, IKUNOSHIN, KUROME, TORU, TAKESAKO, KAZUTOH
Applicants: TAKARA SHUZO CO, TAKARA SHUZO CO. LTD.
Application year: 1994
Main classification: C07K11
IPC codes: A61K38, C07K11